This invention generally relates to a growth factor with dorsal growth inducing activity, and more particularly to a modified form of the Spemann organizer signal Noggin, to compositions comprising the modified Noggin, and to DNA or RNA sequences comprising coding (sense) or antisense sequences for the modified Noggin.
Throughout this application, various publications are referenced. The disclosures of those publications, in their entireties, are hereby incorporated by reference into the subject application.
Growth factors are substances, such as polypeptide hormones, which affect the growth of defined populations of animal cells in vivo or in vitro, but which are not nutrient substances. Proteins involved in the growth or differentiation of tissues may promote or inhibit growth or differentiation, and thus the general term xe2x80x9cgrowth factorxe2x80x9d includes cytokines and trophic factors.
Growth factors, their receptors, DNA or RNA coding or antisense sequences therefore, and fragments thereof, are useful in a number of therapeutic, clinical, research, diagnostic, and drug design applications. See, for example, U.S. Pat. No. 4,857,637, issued Aug. 15, 1989 (method for immunizing an animal against its growth hormone receptor); U.S. Pat. No. 4,933,294, issued Jun. 12, 1990 (assays and therapies involving the human EGF receptor); U.S. Pat. No. 5,030,576, issued Jul. 9, 1991 (the role of receptors and receptor hybrids in drug design and drug screening by the pharmaceutical industry); U.S. Pat. No. 5,087,616, issued Feb. 11, 1992 (method for destroying tumor cells using a composition comprising a growth factor conjugate); U.S. Pat. No. 5,098,833, issued Mar. 24, 1992 (expression systems useful in therapeutic or diagnostic compositions); and International Application Publication No. WO92/05254, published Apr. 2, 1992 (various aspects of isolation, preparation, and applications for a novel neurotrophic factor); each of which is incorporated herein by reference.
The Spemann organizer induces neural tissue from dorsal ectoderm and dorsalizes lateral and ventral mesoderm in Xenopus. The first molecule to have the properties expected of a Spemann organizer signal was identified in an expression screen for activities that induce dorsal structures in Xenopus embryos and was called Noggin (Smith, W. C. and Harland, R. M. Cell 70: 829-840 (1992)). Organizer signals such as Noggin may be antagonized by members of the bone morphogenetic protein (BMP) class of the transforming growth factor beta (TGF-xcex2) gene superfamily. It was recently reported that Noggin protein binds BMP-4 with high affinity and can abolish BMP-4 activity by blocking binding to cognate cell surface receptors (Zimmerman, L. B., et al., Cell 86: 599-606 (1996)).
In addition to their roles in normal bone formation, the BMPs appear to be involved in diseases in which they promote abnormal bone growth. For example, BMPs have been reported to play a causative role in the disease known as Fibrodysplasia Ossificans Progressiva (FOP), in which patients grow an abnormal xe2x80x9csecond skeletonxe2x80x9d that prevents any movement.